Prion diseases are a group of fatal neurodegenerative disorders affecting animals and humans. The central pathogenic event is the conversion of the host-encoded prion protein (PrPC) into a misfolded isoform (PrPSc). PrPSc appears to be the main or sole component of the infectious agent (termed prion) that has the surprising ability to propagate the disease in the absence of nucleic acid. Prions can infect an individual by various routes, including oral ingestion, enter into the body and remain silently replicating in various tissues for a long time before causing a devastating disease in the brain. Our working hypothesis is that several biological processes, including absorption across intestinal barrier, tissue distribution, metabolism, clearance and peripheral prion replication control the fate of PrPSc in the body and determine whether or not the initial oral infection will progress into full-blown disease. The main goal of this project is to study in a detailed and quantitative manner the initial fate of prions upon oral exposure, including the estimation of gut metabolism, intestinal absorption, excretion, whole body tissue distribution, and brain uptake. In addition, we will investigate the gastrointestinal site responsible for prion absorption and the mechanism by which PrPSc penetrates the intestinal barrier. We will also study the effect of prion strains on these parameters in various animal species, including a natural prion host in large animals (cervids). Furthermore, we will study the role of PrPC expression and the interaction of PrPSc with soil particles in its fate upon ingestion in vivo. Finally, we will investigate the dynamic distribution of prions across the entire body during the period from initia infection to the manifestation of the clinical disease. The findings generated in this study will substantially increase our understanding of the mechanism controlling the fate of prions and the pathways implicated in the transport of PrPSc from the mouth to the brain. This data will provide important information to assess the risk of prion contamination in diverse tissues. More importantly, the findings generated in this project will open novel avenues to develop therapeutic strategies aiming for example to prevent prions to be absorbed in the intestine, to decrease uptake into the brain or to increase prion metabolism and elimination.